Insufficient KEAP1-NRF2-ARE signaling reduces glutathione synthesis, quinone detoxification, and peroxide buffering, leaving neurons unable to extinguish mitochondrial and cytosolic ROS once stress begins. The resulting oxidative injury further impairs transcriptional competence and mitochondrial function, creating a permissive feedback architecture. This is a strong systems-level modifier, though less clearly the singular core loop than PARP or ferroptosis models.
Curated pathway from expert analysis
flowchart TD
A["NFE2L2; KEAP1; HMOX1; NQO1; GCLC; TXNRD1<br/>Primary Target"]
B["Biological Process 1<br/>Mechanistic Step A"]
C["Biological Process 2<br/>Mechanistic Step B"]
D["Output Phenotype<br/>Disease Effect"]
A --> B
B --> C
C --> D
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style D fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for NFE2L2; yet. Search RCSB →
Median TPM across 13 brain regions for NFE2L2; KEAP1; HMOX1; NQO1; GCLC; TXNRD1 from GTEx v10.
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for NFE2L2; KEAP1; HMOX1; NQO1; GCLC; TXNRD1.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF NRF2 is deleted selectively in neurons using CamKIIa-Cre;Nfe2l2 flox/flox mice (or silenced via AAV-shNRF2 injected into substantia nigra), THEN baseline mitochondrial H2O2 emission from isolated b | Elevated baseline mitochondrial ROS emission, reduced neuronal NAD+/NADH ratio, and increased protein carbonylation in neuron-specific NRF2-deficient mice | — no observation — | pending | 0.65 |
| IF pharmacological NRF2 activation is achieved via sulforaphane or bardoxolone methyl (30 mg/kg/day oral gavage for 4 weeks starting at disease onset) in the MPTP mouse model of dopaminergic neurodege | Reduced oxidative damage markers (4-HNE adducts, 8-OHdG) and preserved dopaminergic markers (TH+ terminals) in NRF2-activated mice versus vehicle controls | — no observation — | pending | 0.72 |